Dihydrodibenzothiazepines



, piperazyl United States Patent .50 F

. 3,188,321 DEYBE. DEENZGTIHAZEPINE Barry L. Yale, New Brunswick, Francis A. Sowinski, Edison, and Jack Bernstein, New Brunswick, N..l'., assigncrs to 01in Mathieson Chemical Corporation, New York, N.Y., a corporation of Virginia No Drawing. Filed Aug. 3, 1962, Ser. No. 215,546

' salts, include, inter alia, inorganic acids, such as the hydro! The portion of the term of the patent subsequent to Jan 1, H80, has been disclaimed and dedicated '7 Claims. (Cl. 260327) Wherein A is a lower alkylene radical, B is a basic saturated nitrogen-containing radical of less than twelve carbon atoms, and R and R are the same or difierent and represent hydrogen, halogen, lower alkyl, lower alkoXy, trifluoromethyl, trifluoromethylmercapto, trifluoromethoxy or N,N-dimethylaminosulfonyl. Among the suitable radicals represented by the symbol B are: amino; (lower alkylyamino; di(lower alkyl)amino; (hydroxylower alkyl)amino; di(hydroxy-lower alkyl)a'mino; and basic saturated 5 to 7 membered N-heterocyclic radicals of less than twelve carbon atoms, as exemplified by piperidyl [i.e., piperidino, Z-piperidyl, 3-piperidyl and 4-piperidyl]; (lower alkyl)piperidyl [e.g., 2, 3 or 4-(lower alkyDpiperidino or 2,3 or 4-(N-lower -alkyl)-piperidyl]; di(lo/ver alkyDpiperidyl [e.g., 2,4-, 2,5-, or 3,5-di(lower alkyDpiperidino, or 2,3 or 4-(N-lower alkyl)-2,3 or 4-(lower alkyl)piperidyl]; (lower alkoxy)=piperidyl; homopiperidino;

pyrrolidyl; (lower alkyDpyrrolidyl; di(lower alkyDpyrrolidyl; (lower alkoxy)pyrrolidyl, morpholinyl [i.e., morpholino, Z-monpholinyl and 3-morpholinyl]; (lower a-ikyl) morpholinyl; di(lower alkyDrhorpholinyi; (lower alkoxy) morpholinyl; thiamorpholinyl; (lower alkyl)thiamorpholinyl; di(lower alkyl) thiamorpholinyl; (lower alkoxy)thiamorpholinyl; piperazyl; (lower alkyDpiperazyl (e.'g., N

methylpiperazino); di(loWer alkyl) piperazyl; (lower al-.

koxy)piperazyl; (hydroXy-lower alkyDpiperazyl [c.g, N (Z-hydroxyethyl)piperazino]; (lower alkanoyloxyalkyl) [e.g., N -(2-acetoxyethyl)piperazino] droxy-lower BlkOXY-IOWEI alkyl)piperazy1 [e.g., N -(2-hydroxyethoxyethyl) piperazino]; (carbo-lower alkoxy)piperazyl [e.g., bopropoxy)piperazino], and N-homopiperazino. The terms lower alkyl, lower alkoxy, and lower alkylene, as employed herein, include both straight and branched chain radicals of less than eight carbon atoms. The particularly preferred compounds are those wherein A is a lower alkylene radical oftwo to three carbon atoms (i.e., ethylene, trimethylene-l,3 and propylene-1,2); B represents a di(lower alkyDam'ino radical, an N -(lower alkyl) N -(2-carbomethoxy, carboethoxy, or carpiperazino radical, an N -(Z-hydroxyethyl)piperazino radical, or an N -(2-acet oxyethyl)piperazino radical, and R and R are hydrogen.

As to salts of the dihydrodibenzothiazepines, those coming with the purview of this invention include the acidhalic acids (e.g., hydrochloric and hydrobromic acid), sulfuric acid, nitric acid and phosphoric acid, and organic acids, such as'oxalic, maleic, tartaric, citric, acetic and succinic acid.

The compounds of this invention are therapeutically active compounds which are ut-i'lizable both as ataractic agents, and thus may be used in the treatment of depressed psychotic states, and as antihistamines. For these purposes they may be administered orally or parenterally in conventional dosage forms such as tablets, capsules, injectables or the like by incorporating the appropriate dose of the-compound with carriers according to accepted pharmaceutical practice. a

p The compounds of this invention are prepared by the process of this invention with is shown in the following ieiquation, wherein R, R', A and B are as hereinbefore dened:

Suitable starting materials for the process of this invention can be prepared as disclosed in our US. patent application, Serial No. 215,547, filed on even date herewith. These starting materials are treated with a basically substituted lower alkanoyl halide of the formula: B'A--CO halide, wherein B and A are as hereinbefore defined, the reaction preferably being conducted in the presence of a basic condensation reagent, such as sodium hydride, to yield the final products of this invention. The same compounds can alternatively be prepared in two steps, by first reacting with a halo(lower alkanoyl) halide of the formula: (halo)A-CO halide and then with a base of a the formula: BH. To prepare the acid-addition salts, the

resulting base is treated with the desired acid in the usual 2 manner.

The following examples illustrate the invention (all temperatures being in centigrade).

EXAMPLE 1 with Darco, filtered, and the filtrate concentrated to dry ness to give the product.

(1)) PREPARATION OF 2 DIMETHYLAMINOETHYL 5,11

DIHYDRODIBENZO [1),6'] [1,4]1HIAZEPIN-5-YL KETONE A,mixture "of 15.2 g. of -2-chloroethyl '5,11-dihydrodi-' benzo [b,e][1,4]thiazepin-'5-yl ketone, 20.0 g. of anhyaddition salts, particularly, the non-toxic acidaddition salts. Acids useful for preparing the acid-addition .drous dimethylamine andjSO ml. of dry toluene is heated at 60'. for 24 hours. The reaction mixture is cooled, filtered and the filtrate is concentrated to dryness. The residual material is recrystallized from diisopropyl ether Fatented June 8 ,v 1965 3 to give Z-climethylaminoethyl 5,11-clihydrodibenzo[b,e]- 1,4] thiazepine-5-y1 ketone.

EXAMPLE 2 Z-diethylamz'noethyl 5,11 -dihydrodibenz[b,e] [1,4] zhiazepin-S-yl ketone Following the procedure of Example 1 but substituting an equivalent amount of diethylamine for the dimethylamine in step (b), Z-diethylaminoethyl 5,11-dihydrodibenzo [b,e] [1,4] thiazepin-S-yl ketone is obtained.

EXAMPLE 3 Z-dimethylaminoethyl 5,11 -dihydr0dibenz0 b,e] [1,4]thiazepin--yl ketone hydrochloride To a solution of5.92 g. of 2-dimethylaminoethyl-5,11- dihydrodibenzo[b,e][1,-4]thiazepin-5-yl ketone in 25 ml.

of anydrous ether is added 0.75 g. of hydrogen chloride in ml. of anhydrous ether. The precipitated solid is -filtered, dried and recrystallized from acetonitrile-ether to give Z-dimethylaminoethyl 5,11-dihydrodibenzo[b,e]- [1,4]thiazepin-5-yl ketone hydrochloride.

EXAMPLE 4 Z-dimethylaminoethyl 3-chl0ro5,11-dihydr0di benzo[b,e] [1,41thiazepin-5-yl ketone Following the procedure of Example 1, but substituting an equivalent amount of 3-chloro-5,11-dihydrodibenzo- [b,e][1,4]thiazepine for the 5,11-dihydrodibenzo[b,e]- [1,4]thiazepine in step (a), Z-dimethylaminoethyl 3- chloro-5,11-dihydrodibenzo[b,e] [1,4] thiazepin-S-yl ketone is obtained.

EXAMPLE 5 Z-dimethylaminoethyl S-(trifluorornethyl)-5,11-dihydr0dibenzo[b,e] [1,4]thz'azep n-5-yl ketone Following the procedure of Example 1, but substituting an equivalent amount of 3-(trifluoromethyl)-5,1l-dihydrodibenzo[b.e][1,4]thiazepine for the 5,11-dihydrodibenzo [b,e] [1, 4] thiazepine in step (a), Z-dimethylaminaethyl 3-(trifluoromethyl)-5,11-dihydrodibenzo[b,e] [1,4]- thiazepin-S-yl ketone is obtained.

Similarly, by substituting an equivalent amount of 3- (trifluoromethoxy) 5,11 dihydrodibenzo[b,e][1,4]thiazepine, 3-(trifluoromethylmercapto)-5,1l-dihydrodibenzo [b,e] [1,4] thiazepine or 3-(N,N-dimethylaminosulfon-- yl) -5,1l-dihydrodibenzo[b,e] [1,4] thiazepine for the 5,11- dihydrodibenzo[b,e] 1,4]thiazepine in step (a), Example 1, Z-dimethylaminoethyl 3-(trifluoromethoxy)-5,1l-dihydrodibenzo [b,e] ['1 ,4]-thiazepin 5 yl ketone, Z-dimethylaminoethyl 3- (trifluoromethylmercapto -5, 1 l-dihydrodibenzo[b,e] [1,4]thiazepin-5-yl and Z-dimethylarninoethyl 3-(N,N dimethylamino sulfonyl)-5,1l-dihydrodibenzo- [b,e] [1,4]thiazepin-5-yl are prepared, respectively.

EXAMPLE 6 Z-dimethylaminoethyl 7-methyl-5,11-dihydrodibenzo[b,e] [1,4] thz'azepin-S-yl ketone Following the procedure of Example 1, but substituting an equivalent amount of 7-methyl-5,1l-dihydrodrbenzo[b,e] [1,4]thiazepine for the 5,11 dihydrodibenzo[b,e]-

[l,4]thiazepine in step (a), Z-dimethylaminoethyl yl-5,11-dihydrodibenzo[b,e][1,4]thiazepin-5-yl ketone is obtained.

EXAMPLE 7 Z-dimethylaminoethyl 3,7-dichl0ro-5,1I-dihydrodibenzo[b,e] [1,4]thiazepin-5-yl ketone Following the procedure of Example 1, but substituting an equivalent amount of 3,7 -dichloro-5,1l-dlhydrodibenzolbp][1,4 1thiazepine for the 5,11-dihydrodibenzo[b,e] [1,4]thiazepine in step (a), Z-dimethylaminoethyl 3,7 dichloro 5,11-dihydrodibenzo[b,e][1,4]thiazepin- S-yl-ketone is obtained.

EXAMPLE 8 Dimethylaminom ethyl 5 ,1 1-dihydr0dibenzo[b,e]-

[1,4] thzazepin-S-yl ketone Following the procedure of Example 1, but substituting an equivalent amount of chloroacetyl chloride for the fl-chloropr-opionyl chloride in step (a), dimethylaminomethyl 5,11 dihydrodibenzo [b,e] [1,4] thiazepin-S-yl ketone is obtained.

EXAMPLE 9 2- (N -methylpipemzino) ethyl 5 ,1 1 -dihydrodiben- Z0 b,e] [1,4] thiazepin-5-yl ketone EXAMPLE 1O Z-dimethylaminoethyl 7-chl0r0-5,1I-dihydrodibenzo [b,e] [1,4] thiazepin-S-yl ketone Following the procedure of Example 1, step (a), but substituting 12.4 g. of 7-chloro-5,l1-dihydrodibenzo[b,e] [1,4]thiazepine for the 5,11-dihydrodibenzo[b,e] [1,4] thiazepine, there is obtained 2-chloroethyl 7-chloro-5,11- dihydrodibenzo[b,e][1,4]thiazepin-5-yl ketone. Following the procedure of Example 1, step (b), but substituting 17.0 g. of the 2-chloroethyl 7-chloro-5,ll-dihydrodibenzo [b,e] [1,4] thiazepin-S-yl ketone for the 2-chloroethyl-5,11- dihydrodibenzo [b,e] [1,4]thiazepin-5-yl ketone, there is obtained Z-dimethylaminoethyl 7-chloro-5,11-dihydrodibenzo [b,e] [1,4] thiazepin-S-yl ketone.

EXAMPLE 11 2-piperz'din0ethyl 7- (trz'fluoromethyl) -5,11-dihydr0dibenzo [b,e] [1,4] thiazepin-S-yl ketone Following the procedure of Example 1, step (a), but substituting 14.1 g. of 7(trifiuoromethyl)-5,11-dihydrodibenzo[b,e][1,4]thiazepine for the 5,11-dihydrodibenzo [b,e][1,4]thiazepine there is obtained 2-chloroethyl 7- (trifiuoromethyl) 5,11-dihydrodibenzo[b,e][1,4]thiazepin-S-yl ketone. Following the procedure of Example 1, step (b), but substituting 18.6 g. of 2-chloroethyl 7- (trifiuoromethyl) 5,11-dihydrodibenzo[b,e][1,4]thiazepin-S-yl ketone for the 2-chloroethyl 6,11-dihydrodibenzo [b,e][1,4]thiazepin-5-yl ketone and 8.5 g. of anhydrous piperidine for the dirnethylamine, there is obtained 2- piperidinoethyl 7- trifluoromethyl -5 ,1 l-dihydrodibenzo [b,e] [1,4]thiazepin-5-yl ketone.

EXAMPLE 12 Z-dimethylaminoethyl 7-eth0xy-5,ZI-dihydrodibenzo [b,e] [1,4] thiazepine Following the procedure of Example 1, but substituting an equivalent amount of 7-ethoxy-5,1l-dihydrodibenzo [b,e][l,4]thiazepine for the 5,11-dihydrodibenzo[b,e]

[1,4]thiazepine in step (a), Z-dimethylaminoethyl 7-ethoxy-5,11-dihydrodibenzo[b,e] 1,'4]=thiazepine is obtained.

This invention may be variously otherwise embodied within the scope of the appended claims.

What is claimed is:

1. A compound selected from the group consisting of bases of the formula wherein A is lower alkylene, B is a basic saturated nitrogen-containing radical of less than twelve carbon atoms, and R and R are each selected from the group consisting of hydrogen, halogen, lower allryl, lower alkoxy, trifluorornethyl, triflnoromethylmercapto, trifluoromethoxy and N,N-dimethylaminosnlfonyl and non-toxic acid-addition salts thereof.

2. Di(lower alkyl)amino(lower alky1)5,11-dihydrodibenzo [b,e] [1,4]thiazepin-5-yl ketone.

3. A non-toxic acid-addition salt of the compound of claim 2.

4. Z-dimethylaminoethyl 5,11 dihydrodibenzo[b,e] [1,4]thiazepin-5-yl ketone.

6 5. A compound of the formula b-A-(hande oH,s

References Cited by the Examiner UNITED STATES PATENTS 2,485,212 10/49 Miescher et a1. 260-243 2,687,414 8/54 Cusic 260243 3,071,596 1/63 Yale et a1. 260-333 OTHER REFERENCES Hromatka et al.: Monatsh. fiir Chemie, vol. 8-8 (1957), pages 64-71.

WALTER A. MODANCE, Primary Examiner.

NICHOLAS S. RIZZO, Examiner. 

1. A COMPOUND SELECTED FROM THE GROUP CONSISTING OF BSES OF THE FORMULA 